The present invention involves novel compositions of matter. More particularly, the present invention involves novel substituted 2-pyridylmethyl-thio and -sulfinyl benzimidazoles which are useful as gastric antisecretory and cytoprotective agents.
Gastronintestinal inflammatory diseases are characterized by inflammation, specifically by the presence of edema, characteristic inflammatory cells (i.e., leukocytes, histiocytes, and macrophages), and, in some cases, necrosis and ulceration of the surface epithelium. These inflammatory diseases are known to be caused by a wide variety of agents present in the gastrointestinal tract which are known to attack the surfaces thereof, producing the inflammatory disease response. Such agents include micro-organisms (viruses and fungii), bacterial toxins, certain pharmaceutical agents (antibiotics and antiinflammatory steriods), and chemical agents (bile salts, toxic household chemicals). Gastric acid itself is also capable of attacking the stomach lining and producing an inflammatory state.
One means of preventing or treating certain gastrointestinal diseases, specifically gastric diseases, is by the inhibition of gastric acid secretion. In situations where the integrity of the gastric mucosal barrier is compromised, gastric acid secretion can result in erosion of the epithelial cells with consequent inflammation and ulceration. Inhibition of such untoward gastric acid-induced effects can be achieved by the administration of a pharmacological agent effective to inhibit gastric secretion.
One class of such agents effective to inhibit gastric acid secretion are the gastric antisecretory prostaglandins. These substances are known to be effective in the treatment and care of gastric and duodenal ulcers as a result of the inhibition of gastric secretion. See, e.g., U.S. Pat. No. 3,903,297 (Robert, "Method of Treatment and Prophylaxis of Gastric Hypersecretion and Gastric Duodenal Ulcers Using Prostaglandin Analogs"), and Robert, "Antiscretory Property of Prostaglandins," Prostaglandin Symposium of the Worcester Foundation for Experimental Biology 16-17 October 1967, Interscience, New York, page 47 (1968). Another important class of antisecretory agents are the histamine H.sub.2 receptor antagonists, including metiamide and most importantly cimetidine, N-cyano-N'-methyl-N"[2-[[(5-methyl-1H-imidazole-4-yl)methyl]thio]thio]ethy l]guanidine. See, the Merck Index, 9th Edition, Appendix, page App-1 (1976), and Physican's Desk Reference, 36th Edition, 1812-1814 (1982).
Another means of treating such gastrointestinal diseases is through cytoprotection. Certain pharmacological agents have heretofore been known to be useful in exerting a cytoprotective effect on the gastrointestinal tract. This cytoprotective effect is manifest in the ability of such compounds to treat or prevent non-traumatically-induced, non-neoplastic inflammatory disease of the gastrointestinal tract. References describing such cytoprotective effects of prostaglandins are U.S. Pat. No. 4,083,998 (Robert, "Treatment of Inflammatory Diseases of the Mammalian Large Intestine with Cytoprotective Prostaglandins"), issued Apr. 11, 1978; U.S. Pat. No. 4,081,553 (Robert, "Cytoprotective Prostaglandins for Use in Intestinal Diseases"), issued Mar. 28, 1978; and U.S. Pat. No. 4,097,603 (Robert, "Gastric Cytoprotection with Non-Antisecretory Doses of Prostaglandins"), issued June 27, 1978. Gastric cytoprotection is a distinct pharmacological property which is unrelated to gastric antisecretory effects. See, e.g., Robert, U.S. Pat. No. 4,097,603, "Gastric Cytoprotection With Non-Antisecretory Doses of Prostaglandins," Robert, "Cytoprotection by Prostaglandins," Gastroenterology 77:761-767 (1979); Robert, "Current History of Cytoprotection," Prostaglandins 21 (supp):89 (1981), and Robert, et al., "Cytoprotection by Prostaglandins in Rats," Gastroenterology, 77:433-443 (1979). Thus, compounds which are gastric anti-secretory agents may not be cytoprotective agents and vice-versa.